This three-site collaboration has developed a bipolar disorder family resource that has proven to be uniquely valuable in testing clinically based hypotheses about the genetic heterogeneity of the illness. We are ascertaining and assessing 112 additional nuclear families with a bipolar I proband and two or more siblings with a major affective disorder. We will analyze variations in clinical features in the ascertained families, including extending our hypothesis-driven analyses of bipolar II, psychotic bipolar disorder, and panic disorder comorbidity. We are also pursuing data-driven studies to derive and test potentially genetically meaningful phenotypic subtypes. Tests of familial aggregation of variables and factors will be performed, and positive results will be followed by covariate analyses of linkage results. [unreadable] [unreadable] A new genome-wide linkage scan has been performed by the Center for Inherited Disease Research (CIDR) on 105 families not previously scanned. An additional 112 families will be scanned this coming year, the 5th and final year of this project. The data will be analyzed both with standard linkage methods and with conditional logistic methods that allow for use of covariates such as clinical variables or factors, or other loci. The linkage data generated in year 1 will, among other things, provide a replication sample for the genotype-subphenotype studies referred to above. [unreadable] [unreadable] We have also performed association studies through SNP genotyping (using the Illumina platform) in 4 chromosomal regions: 6q21-23, 13q31-33, 18q21-22 and 22q12. Analyses of the SNP data have revealed several signals that we are following up with replication in an independent sample. Replicated findings will be pursued through sequencing for mutation analysis and rare SNP discovery. [unreadable] [unreadable] During the past year, we have reported results of an association study of close to 5000 SNP markers on chromosomes 13, 18, and 22, as well as in selected candidate genes. Preliminary results implicate several genes in bipolar disorder that are good candidates for replication in independent samples. One of these, GRM7, encodes a metabotropic glutamate receptor that has previously been implicated in schizophrenia. We plan to collaborate with schizophrenia researchers in following up this finding in additional samples.[unreadable] [unreadable] We have also generated a database of clinical variables, The Bipolar Disorder Phenome Database, based in part on this sample. The database contains over 100 variables, harmonized with those collected by the NIMH Genetics Initiative, describing the course, symptoms, and clinical picture of bipolar disorder. We have made the database available to the scientific community to support research into the genetics of bipolar disorder and related conditions.